Gang-Yi Wu, Ph.D.
Assistant Professor
Ph.D., Institute of Biophysics, Academia Sinica, P. R. China
Postdoctoral, Cold Spring Harbor Labs and Stanford University
E-mail: gangyiw@bcm.edu
Telephone: 713-798-5429
Fax: 713-798-3475
Research Focus
Current research centers on Cell Signaling and Activity-dependent Neuronal Plasticity to obtain a better understanding of the signaling networks underlying activity-dependent changes in the brain, processes of immense basic science and clinical significance.
Activity-dependent modification of neuronal circuitry in principle provides a means by which experience can influence the number and pattern of synaptic connections, and ultimately an animal's behavioral repertoire. Indeed, it is now widely believed that activity-dependent processes underlie a broad range of relevant physiological and pathological phenomena, including early development of specific synaptic connections, learning and memory, chronic pain, epilepsy, dementia, and long-term drug abuse and addiction. We have developed model systems suitable for high-resolution time-lapse imaging of single neurons over periods of days, and manipulation of proteins by gene transfection, as well as whole cell patch recording both in vivo and in vitro. These model systems have proved to be very useful for effectively characterizing the candidate signals and signal transduction components underlying stable activity-dependent changes in the CNS.
The long-term goal of our research is to delineate the cellular mechanisms and signaling transduction pathways underlying dendritic spine formation and plasticity, using imaging, molecular genetic, and biochemical approaches. Dendritic spines, the primary targets of excitatory synaptic inputs, are potential sites of both biochemical and structural synaptic plasticity. However, the signaling transduction pathways underlying activity-dependent changes in synapses are largely unknown. The evolutionarily conserved Ras-MAPK signaling cascade regulates many important cellular processes including gene expression, cell proliferation, cell survival and death, and cell motility. A recent set of studies suggests that the Ras-MAPK signaling cascade is critical for both memory consolidation and long-term synaptic plasticity. Using a unique dentate gyrus explant culture system, we have demonstrated that repeated, spaced membrane depolarizations produce a persistent activation of MAPK signaling and formation of dendritic filopodia and spines that are associated with enduring remodeling of synapses and induction of long-term synaptic plasticity.
One line of our current research aims at understanding the cellular and molecular basis of learning deficits in neurofibromatosis type1 (NF1). NF1 is a common dominant genetic disorder characterized by multiple benign and malignant tumors of neural origin and, often, cognitive deficits in children. The protein encoded by NF1, neurofibromin, contains a GAP domain, known to inhibit Ras-mediated signal transduction. Recent evidence demonstrates that NF1 interacts with synaptic protein complexes, which may link NF1 to a critical signaling network underlying synapse formation and function. We are testing the hypothesis that, although Ras-MAPK signaling is involved in the initiation of dendritic filopodia, a spatiotemporal shutting-off of its activity is required for stabilization and development of fully functional dendritic spines. Multidisciplinary approaches, including time-lapse imaging confocal microscopy, molecular imaging with FRET, quantitative immunocytochemistry, whole-cell patch-clamp recording, genetic mouse models, and pharmacological and molecular manipulations such as dominant negative constructs and small interfering RNAs (siRNAs), will be used to define the NF1 function in synapse formation and morphogenesis of dendritic spines.
Another line of our research centers on elucidating the role of the Ras-PI3K-AKT-mTOR pathway, another major Ras downstream pathway in the regulation of neuronal morphology, particularly in dendritic spine formation and plasticity. Our recent results revealed an unexpected central role of this signaling pathway in the regulation of many aspects of neuronal morphogensis. This is particularly interesting, as genetic defects of the Ras-PI3K-AKT-mTOR signaling pathway, either through genetic inheritance or as a spontaneous genetic mutation are associated with various human diseases. Mutations in PTEN and TSC1/2, two other tumor suppressor genes known key regulators for PI3K-AKT-mTOR signaling are associated with the alteration of Ras-PI3K-AKT signaling and tumorigenesis and, often, with mental retardation. Given that there is growing evidence suggesting a link between dendritic spine remodeling and human cognition and mental retardation, our study will contribute significantly to our understanding of the fundamental mechanisms of learning and memory in general and the pathological basis of the cognition deficits seen in these devastating diseases. The information obtained will become the basis for a future study to develop therapeutic interventions to treat the cognitive deficits seen in those patients with mental retardation.